Cardiovascular disease is the number one killer of Americans, claiming over 500,000 lives annually. These deaths occur when the fibrous cap of an atherosclerotic plaque ruptures in the later stages of the disease. Current screening tests for the diagnosis of coronary atherosclerosis is limited. Coronary angiography, the gold standard employed to assess the severity of coronary disease in symptomatic patients, reveals only the degree of luminal narrowing, and fails to visualize the arterial wall. Additionally, arterial remodeling prevents many plaques from being detected by coronary angiography. The overall goal of this proposal is to develop two pragmatic ultrasound-imaging techniques (neovascular imaging, and elastography imaging) to identify life threatening atherosclerotic plaques. The microvascular networks or vasa vasorum of developing atherosclerotic plaques may function as a conduit for the migration of leukocytes and plasma components into the arterial wall or into the endothelium on the arterial surface. These inflammatory cells, if allowed to accumulate, will weaken the fibrous cap. The resolution of intravascular ultrasound (IVUS) is not sufficiently high to visualize plaque neovasculature; therefore, we propose to develop a microbubble ultrasound contrast that binds preferentially to newly formed blood vessels. More specifically, we propose to conjugate a microbubble contrast agent to a peptide with the NGR-homing sequence that binds to CD13, and a monoclonal antibody, DC101, that binds to the VEGF receptor-2. The conjugated microbubbles will be visualized by employing the second harmonic contrast imaging mode, which we propose to implement on a commercial ultrasound IVUS scanner. The mechanical behavior of stable plaques is noticeably different from those of stable plaques. Circumferential stress will accumulate at the junction between the normal intima, and the fibrous cap overlaying the lipid pool in unstable plaques; whereas this does not occur in stable plaques. To differentiate between stable and unstable plaques based on their mechanical behavior we propose to visualize the stress distribution within vascular tissue using a novel prototype system for intravascular ultrasonic elastographic imaging. An atherosclerotic animal model will be employed to assess a) the sensitivity and specificity of detecting life-threatening plaques with both imaging approaches as standalone methods will be assessed relative to a combined microvascular-elastography imaging approach, and b) the feasibility of predicting the propensity of plaque to rupture based on the three imaging approaches. A successful out come of the proposed may prove to be beneficial to the over 50 million Americans who are unaware that they may be suffering from advance coronary atherosclerosis and should be placed on a lipid-lowering dietary and pharmacological treatment.